Zhongxin Zhu

Psoriasis is a chronic inflammatory dermatosis characterized by pathological keratinocyte hyperproliferation and dysregulated immune activation. While ubiquitin-specific peptidase 16 (USP16) has been implicated in modulating multiple cellular signaling pathways, its functional role in psoriatic pathogenesis remains poorly understood. Our investigation revealed pronounced upregulation of USP16 expression in psoriatic epidermis compared with normal controls. Keratinocyte-specific USP16 knockdown demonstrated remarkable therapeutic efficacy, significantly ameliorating characteristic psoriatic phenotypes including epidermal hyperplasia and inflammatory infiltration. RNA-seq analysis showed that USP16 has substantial effects on cell cycle transition and keratinocytes proliferation. Through KEGG analysis, it was found that USP16 primarily regulates the NLRP3 signaling pathway, leading to enhanced cell proliferation and inflammation. Mechanically, USP16 directly binds to the NLRP3 protein to eliminate K48 ubiquitination modification, enhancing the stability of the NLRP3 protein, activating inflammasome activity. Further studies showed that the therapeutic effects of reducing USP16 on psoriasis progression were counteracted by an NLRP3 activator and keratinocyte-specific NLRP3 overexpression adenovirus. Collectively, these results shed light on how USP16 promotes NLRP3 signaling in keratinocytes, exacerbating psoriasis development. This positive regulation highlights the potential of USP16 as a therapeutic target for psoriasis.

Psoriasis is a chronic skin disease characterized by abnormal proliferation and inflammation of epidermal keratinocytes. Fibroblast growth factor 12 (FGF12) is implicated in the regulation of diverse cellular signals; however, its precise mechanism in psoriasis requires further investigation. In this study, high expression of FGF12 is observed in the epidermis of skin lesion in psoriasis patients and imiquimod (IMQ)‐induced psoriasis like‐dermatitis. Moreover, specific loss of FGF12 in keratinocytes in IMQ‐induced psoriasis model alleviates psoriasis‐like symptoms and reduces proliferation. In vitro RNA sequencing demonstrates that knockdown of FGF12 effectively arrests the cell cycle, inhibits cell proliferation, and predominantly regulates the p53 signaling pathway. Mechanistically, FGF12 is selectively bound to the RING domain of MDM2, thus partially inhibiting the binding of β‐Trcp to MDM2. This interaction inhibits β‐Trcp‐induced‐K48 ubiquitination degradation of MDM2, thereby suppressing the activity of the p53 signaling pathway, which results in excessive cell proliferation. Last, the alleviatory effect of FGF12 deficiency on psoriasis progression is reversed by p53 knockdown. In summary, these findings provide valuable insights into the mechanisms by which FGF12 suppresses p53 signaling in keratinocytes, exacerbating the development of psoriasis. This positive regulatory loop highlights the potential of FGF12 as a therapeutic target to manage psoriasis.

Skin wound healing is a complex and organized biological process, and the dermal fibroblasts play a crucial role. α‐Catenin is known to be involved in regulating various cellular signals, and its role in wound healing remains unclear. Here, we have identified the pivotal role of the α‐catenin/FAK/YAP signaling axis in the proliferation and migration of dermal fibroblasts, which contributes to the process of skin wound healing. Briefly, when α‐catenin was knocked down specifically in dermal fibroblasts, the wound healing rate is significantly delayed. Moreover, interfering with α‐catenin can impede the proliferation and migration of dermal fibroblasts both in vitro and in vivo. Mechanistically, the overexpression of α‐catenin upregulates the nuclear accumulation of YAP and transcription of downstream target genes, resulting in enhanced the proliferation and migration of dermal fibroblasts. Furthermore, the FAK Tyr397 phosphorylation inhibitor blocked the promoting effects of α‐catenin on YAP activation. Importantly, the continuous phosphorylation mutation of FAK Tyr397 reversed the retardatory effects of α‐catenin knockdown on wound healing, by increasing the vitality of fibroblasts. Likewise, α‐catenin/FAK was validated as a therapeutic target for wound healing in the db/db chronic trauma model. In summary, our findings have revealed a novel mechanism by which α‐catenin facilitates the function of fibroblasts through the activity of the FAK/YAP signaling axis. These findings define a promising therapeutic strategy for accelerating the wound healing process.

Background and Purpose: Migration and differentiation of epidermal cells are essential for epidermal regeneration during wound healing. Fibroblast growth factor 21 (FGF21) plays key roles in mediating a variety of biological activities. However, its role in skin wound healing remains unknown.Experimental Approach: Fgf21 knockout (Fgf21 KO) mice were used to determine the effect of FGF21 on wound healing. The source of FGF21 and its target cells were determined by immunohistochemistry, immunoblotting, and ELISA assay. Moreover, Sirt1^flox/flox and Atg7^flox/flox mice were constructed and injected with the epidermal‐specific Cre virus to elucidate the underlying mechanisms. Migration and differentiation of keratinocytes were evaluated in vitro by cell scratch assays, immunofluorescence, and qRT‐RCR. The effects were further assessed when SIRT1, ATG7, ATG5, BECN1, and P53 were silenced. Interactions between SIRT1 and autophagy‐related genes were assessed using immunoprecipitation assays.Key Results: FGF21 was active in fibroblasts and promoted migration and differentiation of keratinocytes following injury. After wounding, SIRT1 expression and autophagosome synthesis were lower in Fgf21 KO mice. Depletion of ATG7 in keratinocytes counteracted the FGF21‐induced increases in migration and differentiation, suggesting that autophagy is required for the FGF21‐mediated pro‐healing effects. Furthermore, epithelial‐specific Sirt1 knockout abolished the FGF21‐mediated improvements of autophagy and wound healing. Silencing of SIRT1 in keratinocytes, which decreased deacetylation of p53 and autophagy‐related proteins, revealed that FGF21‐induced autophagy during wound healing was SIRT1‐dependent.Conclusions and implications: FGF21 is a key regulator of keratinocyte migration and differentiation during wound healing. FGF21 may be a novel therapeutic target to accelerate would healing.